tbuckley/cabot-search huggingface dataset:
POS0925 AUTOMATIC SCORING OF ULTRASOUND SYNOVIAL HYPERTROPHY IN RHEUMATOID ARTHRITIS THROUGH INTEGRATING MULTIPLE CONVOLUTIONAL NEURAL NETWORK MODELS
Authors: C. C. Huang, P. Huang, K. J. Yeo, C. J. Chang, K. C. Wu, W. J. Hong, S. H. Chang, J. L. Lan, D. Y. Chen, C. H. Kao
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> The OMERACT-EULAR Synovitis Scoring (OESS) system is worldwide used to evaluate arthritis severity on ultrasound (US) images. Because of inter-observer and intra-observer variability, deep learning (DL) has been applied in high-quality image interpretation and analysis. Previous studies mostly focused on Doppler US (DUS) classification by convolutional neural network (CNN), which could provide objective assessment. However, the reports of DL intervention in grey scale (GS) US image automatic measurements are limited. <h3>Objectives</h3> The aim of this study was to develop an integrated multiple CNN model in precise scoring GS US images from rheumatoid arthritis (RA) patients. <h3>Methods</h3> The standard US images from patients of RA were retrospectively selected by three 10-years US experienced rheumatologist together and were graded according to the OESS system. Six different joints data were taken, including proximal interphalangeal, metacarpophalangeal, wrist, elbow, knee and ankle joints. We conducted the DL model integrating three binary CNNs to predict four-class GS US scoring (Figure 1). The accuracy of the trained model was tested by an independent test data. <h3>Results</h3> Total 678 images from 447 patients of RA were used in this study. These images were divided into training (n=611) and testing (n=67) sets. The integrated multiple CNNs model could achieve a four-class accuracy of 77.6%. The individual accuracy of grades 0, 1, 2 and 3 were 68.4%, 77.3%, 73.3% and 100%, respectively (Table 1). Furthermore, we found that adding on anatomic site parameters or labeling areas of interest would establish a better average area under curve (AUC) with 92.6% and 89.0%. <h3>Conclusion</h3> Our study suggests the possibility of using the integrated multiple CNNs model in grading synovial hypertrophy of RA, which is critical in RA healthcare. External validation would be required to confirm the predictive ability of this model. <h3>References</h3> [1]D'Agostino MA et al. RMD Open. 2017 Jul 11;3(1):e000428. [2]Andersen JKH et al. RMD Open. 2019 Mar 30;5(1):e000891. [3]Christensen ABH et al. Ann Rheum Dis. 2020 Sep;79(9):1189-1193. [4]Shin Y et al. Ultrasonography. 2021 Jan;40(1):30-44. [5]Zhou Z et al. Patterns (N Y). 2022 Sep 29;3(10):100592. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.
POS0865 THE CORRELATION BETWEEN FOUR ADHERENCE MEASUREMENTS METHODS IN PATIENTS WITH RHEUMATOID ARTHRITIS USING METHOTREXATE
Authors: R. Hebing, N. Elhendy, E. Van Geel, M. Van Heuckelum, M. T. Nurmohamed, B. Van den Bemt
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> Methotrexate (MTX) is the cornerstone in the pharmacological treatment of rheumatoid arthritis (RA) patients. However, medication adherence to MTX is not ideal, which might lead to suboptimal treatment outcomes. Consequently instruments to assess medication non-adherence are warranted to detect and intervene on non-adherence. To date there is no consensus on the best method to determine adherence to MTX. <h3>Objectives</h3> The aim of this study was to assess the correlation between compliance measured with MEMS (gold standard) versus pill count, MTX-polyglutamate (PG) concentration and Compliance Questionnaire Rheumatology (CQR) in patients with established RA. Second, correlations between these methods and the Disease Activity Scores of 28 joints (DAS28) were examined. <h3>Methods</h3> Adult patients with established RA treated with MTX were included. Multivariable linear and logistic regression were used, with taking compliance assessed with MEMS as dependent variable versus pill count, MTX-PG concentrations, CQR, as independent variables, and DAS28 score versus each of the 4 adherence measurements methods. Comedication, age and use of corticosteroids and NSAIDs were included as covariates in the analysis. <h3>Results</h3> 190 consecutive RA patients were included. Median follow-up time was 4.9 months (IQR 3.6 – 6.2). Pill count correlated with taking compliance assessed with MEMS (linear regression, β =.690, p = &lt;.001), whereas MTX-PG concentrations and CQR were not. Logistic regression only confirmed the correlation between dichotomized taking compliance MEMS and pill count (β = 5.64, p =.001). No other correlations were found. Between adherence outcomes and DAS28 scores no correlations were seen. <h3>Conclusion</h3> Taking compliance measured with MEMS was correlated with pill count, whereas other methods were not correlated with MEMS, nor with DAS28. Pill count can be used to estimate adherence to MTX therapy, when MEMS is not feasible. <h3>REFERENCES:</h3> NIL. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.
POS0897 THE PERFORMANCE OF COMBINING EYE SIGN AND FUNCTIONAL MAGNETIC RESONANCE IMAGING IN DIAGNOSING PATIENTS WITH NEUROPSYCHIATRIC SYSTEMIC LUPUS ERYTHEMATOSUS
Authors: J. L. H. Shi
Journal: Annals of the Rheumatic Diseases (2023)

<h3>Background</h3> The diagnosis of NPSLE becomes challenging for rheumatologists, both at a diagnostic and therapeutic level. The 1999 ACR criteria had a high sensitivity (91%), but a low specificity (46%) [1]. <h3>Objectives</h3> To investigate the alterations of eye sign and functional magnetic resonance imaging (fMRI) in patients with neuropsychiatric systemic lupus erythematosus (NPSLE) and to explore the performance of combining eye sign and MRI in diagnosing NPSLE. <h3>Methods</h3> In phase 1, SLE patients were consecutively recruited Sep 2017 to Sep 2018 including NPSLE patients and non-NPSLE patients. Eye sign examination for bulbar conjunctival microvascular were performed for all SLE patients and fMRI scanning for NPSLE patients. Demographic and clinical data were compared between two groups and to identify potential predictors for NPSLE by using multivariable logistic regression analysis. In phase 2, NPSLE patients in phase 1 were enrolled, and a new diagnostic algorithm including predictors and changed fMRI parameters was designed with the 1999 NPSLE ACR classification as comparison. Expert opinion was considered as golden standard. Double-blind clinical diagnosis from expert were recorded using new algorithm and 1999 ACR classification, respectively. Area under the curve (AUC) under receiver operating characteristic (ROC) curve, sensitivity and specificity were calculated and compared between these two diagnostic methods. <h3>Results</h3> 120 SLE patients were recruited (32.99±1.03 years) including 45 NPSLE and 90 non-NPSLE. NPSLE had higher disease activity (reflected as SLEDAI and ESR). Compared with Non-NPSLE group, fMRI showed changed fALFF and ReHo in brain regions relevant to cognition and emotion (p&lt;0.01). Eye sign examination showed NPSLE group had significantly higher scores of ramified loops, vascular tone, microangioma, wound point and had higher total scores than non-NPSLE group (p&lt;.001). In multivariable logistic analysis, SLEDAI, ramified loop, microangioma, wound point and presence of antiphospholipid antibodies were predictors of NPSLE (Table 1). the AUC of the ACR classification under ROC curve was 0.775, sensitivity was 75.0%, specificity was 80.0% (p=0.002), the AUC of new algorithm under ROC curve was 0.815, sensitivity was 75.0%, specificity was 88.0% (p&lt;.001) (Figure 1). <h3>Conclusion</h3> This proposed new algorithm showed not to be inferior to the 1999 ACR classification and need to be confirmed in further studies. <h3>Reference</h3> [1]West SG. Clinical aspects of the nervous system. In: Wallace DJ, Hahn BH, editors. Dubois' Lupus Erythematosus and Related Syndromes. Vol. 2013. Philadelphia: Saunders; pp. 368–81. <h3>Acknowledgements:</h3> NIL. <h3>Disclosure of Interests</h3> None Declared.
The Incidentally Discovered Adrenal Mass
Authors: PAUL M. COPELAND
Journal: Annals of Internal Medicine (1983)

With the wider application of increasingly sensitive computed tomographic scans, more adrenal masses will be discovered incidentally. Because benign lesions of the adrenal are much commoner than malignant ones, an approach is needed to determine which incidentally discovered masses should be removed. The history and physical examination may guide the evaluation. Imaging studies and needle biopsies have limited value. If the history and physical findings do not suggest a diagnosis, an approach using the size of the mass, results of any cyst puncture, and a biochemical assessment may determine which patients should have surgery. This approach is based on the relative prevalences of benign and malignant clinically silent adrenal tumors.
Smaller size packs a stronger punch - Recent advances in small antibody fragments targeting tumour-associated carbohydrate antigens
Authors: Sana Khan Khilji, Charlotte Op 't Hoog, David Warschkau, Jost Lühle, Felix Goerdeler, Anika Freitag, Peter H. Seeberger, Oren Moscovitz
Journal: Theranostics (2023)

Attached to proteins, lipids, or forming long, complex chains, glycans represent the most versatile post-translational modification in nature and surround all human cells.Unique glycan structures are monitored by the immune system and differentiate self from non-self and healthy from malignant cells.Aberrant glycosylations, termed tumour-associated carbohydrate antigens (TACAs), are a hallmark of cancer and are correlated with all aspects of cancer biology.Therefore, TACAs represent attractive targets for monoclonal antibodies for cancer diagnosis and therapy.However, due to the thick and dense glycocalyx as well as the tumour micro-environment, conventional antibodies often suffer from restricted access and limited effectiveness in vivo.To overcome this issue, many small antibody fragments have come forth, showing similar affinity with better efficiency than their full-length counterparts.Here we review small antibody fragments against specific glycans on tumour cells and highlight their advantages over conventional antibodies.
Cryo-shocked cancer cell microgels for tumor postoperative combination immunotherapy and tissue regeneration
Authors: Gaizhen Kuang, Qingfei Zhang, Yunru Yu, Luoran Shang, Yuanjin Zhao
Journal: Bioactive Materials (2023)

Prevention of recurrence/metastasis and tissue regeneration are critical for post-surgery treatment of malignant tumors. Here, to address these needs, a novel type of microgel co-loading cryo-shocked cancer cells, immunoadjuvant, and immune checkpoint inhibitor is presented by microfluidic electrospray technology and liquid nitrogen treatment. Owing to the encapsulation of cryo-shocked cancer cells and immunoadjuvant, the microgels can recruit dendritic cells and activate them
Adavosertib Enhances Antitumor Activity of Trastuzumab Deruxtecan in HER2-Expressing Cancers
Authors: Timothy P. DiPeri, Kurt W. Evans, Maria Gabriela Raso, Ming Zhao, Yasmeen Q. Rizvi, Xiaofeng Zheng, Bailiang Wang, Bryce P. Kirby, Kathleen Kong, Michael Kahle, Timothy A. Yap, Ecaterina E. Dumbrava, Jaffer A. Ajani, Siqing Fu, Khandan Keyomarsi, Funda Meric-Bernstam
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Cyclin E (CCNE1) has been proposed as a biomarker of sensitivity to adavosertib, a Wee1 kinase inhibitor, and a mechanism of resistance to HER2-targeted therapy. Experimental Design: Copy number and genomic sequencing data from The Cancer Genome Atlas and MD Anderson Cancer Center databases were analyzed to assess ERBB2 and CCNE1 expression. Molecular characteristics of tumors and patient-derived xenografts (PDX) were assessed by next-generation sequencing, whole-exome sequencing, fluorescent in situ hybridization, and IHC. In vitro, CCNE1 was overexpressed or knocked down in HER2+ cell lines to evaluate drug combination efficacy. In vivo, NSG mice bearing PDXs were subjected to combinatorial therapy with various treatment regimens, followed by tumor growth assessment. Pharmacodynamic markers in PDXs were characterized by IHC and reverse-phase protein array. Results: Among several ERBB2-amplified cancers, CCNE1 co-amplification was identified (gastric 37%, endometroid 43%, and ovarian serous adenocarcinoma 41%). We hypothesized that adavosertib may enhance activity of HER2 antibody–drug conjugate trastuzumab deruxtecan (T-DXd). In vitro, sensitivity to T-DXd was decreased by cyclin E overexpression and increased by knockdown, and adavosertib was synergistic with topoisomerase I inhibitor DXd. In vivo, the T-DXd + adavosertib combination significantly increased γH2AX and antitumor activity in HER2 low, cyclin E amplified gastroesophageal cancer PDX models and prolonged event-free survival (EFS) in a HER2-overexpressing gastroesophageal cancer model. T-DXd + adavosertib treatment also increased EFS in other HER2-expressing tumor types, including a T-DXd–treated colon cancer model. Conclusions: We provide rationale for combining T-DXd with adavosertib in HER2-expressing cancers, especially with co-occuring CCNE1 amplifications. See related commentary by Rolfo et al., p. 4317
A Bifunctional PARP-HDAC Inhibitor with Activity in Ewing Sarcoma
Authors: Louise Ramos, Sarah Truong, Beibei Zhai, Jay Joshi, Fariba Ghaidi, Michael M. Lizardo, Taras Shyp, Sonia H.Y. Kung, Alireza M. Rezakhanlou, Htoo Zarni Oo, Hans Adomat, Stephane Le Bihan, Colin Collins, Jeffrey Bacha, Dennis Brown, John Langlands, Wang Shen, Nada Lallous, Poul H. Sorensen, Mads Daugaard
Journal: Clinical Cancer Research (2023)

Abstract Purpose: Histone deacetylase (HDAC) inhibition has been shown to induce pharmacologic “BRCAness” in cancer cells with proficient DNA repair activity. This provides a rationale for exploring combination treatments with HDAC and PARP inhibition in cancer types that are insensitive to single-agent PARP inhibitors (PARPi). Here, we report the concept and characterization of a novel bifunctional PARPi (kt-3283) with dual activity toward PARP1/2 and HDAC enzymes in Ewing sarcoma cells. Experimental Design: Inhibition of PARP1/2 and HDAC was measured using PARP1/2, HDAC activity, and PAR formation assays. Cytotoxicity was assessed by IncuCyte live cell imaging, CellTiter-Glo, and spheroid assays. Cell-cycle profiles were determined using propidium iodide staining and flow cytometry. DNA damage was examined by γH2AX expression and comet assay. Inhibition of metastatic potential by kt-3283 was evaluated via ex vivo pulmonary metastasis assay (PuMA). Results: Compared with FDA-approved PARP (olaparib) and HDAC (vorinostat) inhibitors, kt-3283 displayed enhanced cytotoxicity in Ewing sarcoma models. The kt-3283-induced cytotoxicity was associated with strong S and G2–M cell-cycle arrest in nanomolar concentration range and elevated DNA damage as assessed by γH2AX tracking and comet assays. In three-dimensional spheroid models of Ewing sarcoma, kt-3283 showed efficacy in lower concentrations than olaparib and vorinostat, and kt-3283 inhibited colonization of Ewing sarcoma cells in the ex vivo PuMA model. Conclusions: Our data demonstrate the preclinical justification for studying the benefit of dual PARP and HDAC inhibition in the treatment of Ewing sarcoma in a clinical trial and provides proof-of-concept for a bifunctional single-molecule therapeutic strategy.
Domino-like effect of C112R mutation on ApoE4 aggregation and its reduction by Alzheimer’s Disease drug candidate
Authors: Michal Nemergut, Sérgio M. Marques, Lukas Uhrik, Tereza Vanova, Marketa Nezvedova, Darshak Chandulal Gadara, Durga Jha, Jan Tulis, Veronika Novakova, Joan Planas-Iglesias, Antonin Kunka, Anthony Legrand, Hana Hribkova, Veronika Pospisilova, Jiri Sedmik, Jan Raska, Zbynek Prokop, Jiri Damborsky, Dasa Bohaciakova, Zdenek Spacil, Lenka Hernychova, David Bednar, Martin Marek
Journal: Molecular Neurodegeneration (2023)

Abstract Background Apolipoprotein E (ApoE) ε4 genotype is the most prevalent risk factor for late-onset Alzheimer’s Disease (AD). Although ApoE4 differs from its non-pathological ApoE3 isoform only by the C112R mutation, the molecular mechanism of its proteinopathy is unknown. Methods Here, we reveal the molecular mechanism of ApoE4 aggregation using a combination of experimental and computational techniques, including X-ray crystallography, site-directed mutagenesis, hydrogen-deuterium mass spectrometry (HDX-MS), static light scattering and molecular dynamics simulations. Treatment of ApoE ε3/ε3 and ε4/ε4 cerebral organoids with tramiprosate was used to compare the effect of tramiprosate on ApoE4 aggregation at the cellular level. Results We found that C112R substitution in ApoE4 induces long-distance (&gt; 15 Å) conformational changes leading to the formation of a V-shaped dimeric unit that is geometrically different and more aggregation-prone than the ApoE3 structure. AD drug candidate tramiprosate and its metabolite 3-sulfopropanoic acid induce ApoE3-like conformational behavior in ApoE4 and reduce its aggregation propensity. Analysis of ApoE ε4/ε4 cerebral organoids treated with tramiprosate revealed its effect on cholesteryl esters, the storage products of excess cholesterol. Conclusions Our results connect the ApoE4 structure with its aggregation propensity, providing a new druggable target for neurodegeneration and ageing. Graphic Abstract
Epiphany: predicting Hi-C contact maps from 1D epigenomic signals
Authors: Rui Yang, Arnav Das, Vianne R. Gao, Alireza Karbalayghareh, William S. Noble, Jeffrey A. Bilmes, Christina S. Leslie
Journal: Genome biology (2023)

Abstract Recent deep learning models that predict the Hi-C contact map from DNA sequence achieve promising accuracy but cannot generalize to new cell types and or even capture differences among training cell types. We propose Epiphany, a neural network to predict cell-type-specific Hi-C contact maps from widely available epigenomic tracks. Epiphany uses bidirectional long short-term memory layers to capture long-range dependencies and optionally a generative adversarial network architecture to encourage contact map realism. Epiphany shows excellent generalization to held-out chromosomes within and across cell types, yields accurate TAD and interaction calls, and predicts structural changes caused by perturbations of epigenomic signals.
The role of neutrophils in alcohol-related hepatitis
Authors: Reenam S. Khan, Patricia F. Lalor, Mark Thursz, Philip N. Newsome
Journal: Journal of Hepatology (2023)

Alcohol-related liver disease is a major cause of liver disease-associated mortality, with inpatient care being a major contributor to its clinical and economic burden. Alcohol-related hepatitis (AH) is an acute inflammatory form of alcohol-related liver disease. Severe AH is associated with high short-term mortality, with infection being a common cause of death. The presence of AH is associated with increased numbers of circulating and hepatic neutrophils. We review the literature on the role of neutrophils in AH. In particular, we explain how neutrophils are recruited to the inflamed liver and how their antimicrobial functions (chemotaxis, phagocytosis, oxidative burst, NETosis) may be altered in AH. We highlight evidence for the existence of 'high-density' and 'low-density' neutrophil subsets. We also describe the potentially beneficial roles of neutrophils in the resolution of injury in AH through their effects on macrophage polarisation and hepatic regeneration. Finally, we discuss how manipulation of neutrophil recruitment/function may be used as a therapeutic strategy in AH. For example, correction of gut dysbiosis in AH could help to prevent excess neutrophil activation, or treatments could aim to enhance miR-223 function in AH. The development of markers that can reliably distinguish neutrophil subsets and of animal models that accurately reproduce human disease will be crucial for facilitating translational research in this important field.
Evidence-based hyponatremia management in liver disease
Authors: Ji Young Ryu, Seon Ha Baek, Sejoong Kim
Journal: Clinical and Molecular Hepatology (2023)

Hyponatremia is primarily a water balance disorder associated with high morbidity and mortality. The pathophysiological mechanisms behind hyponatremia are multifactorial, and diagnosing and treating this disorder remains challenging. In this review, the classification, pathogenesis, and step-by-step management approaches for hyponatremia in patients with liver disease are described based on recent evidence. We summarize the five sequential steps of the traditional diagnostic approach: 1) confirm true hypotonic hyponatremia, 2) assess the severity of hyponatremia symptoms, 3) measure urine osmolality, 4) classify hyponatremia based on the urine sodium concentration and extracellular fluid status, and 5) rule out any coexisting endocrine disorder and renal failure. Distinct treatment strategies for hyponatremia in liver disease should be applied according to the symptoms, duration, and etiology of disease. Symptomatic hyponatremia requires immediate correction with 3% saline. Asymptomatic chronic hyponatremia in liver disease is prevalent and treatment plans should be individualized based on diagnosis. Treatment options for correcting hyponatremia in advanced liver disease may include water restriction; hypokalemia correction; and administration of vasopressin antagonists, albumin, and 3% saline. Safety concerns for patients with liver disease include a higher risk of osmotic demyelination syndrome.
Neuroprotective protein ADNP-dependent histone remodeling complex promotes T helper 2 immune cell differentiation
Authors: Ana C.F. Ferreira, Aydan C.H. Szeto, Paula A. Clark, Alastair Crisp, Patrycja Kozik, Helen E. Jolin, Andrew N.J. McKenzie
Journal: Immunity (2023)

Type 2 immune responses are critical in tissue homeostasis, anti-helminth immunity, and allergy. T helper 2 (Th2) cells produce interleukin-4 (IL-4), IL-5, and IL-13 from the type 2 gene cluster under regulation by transcription factors (TFs) including GATA3. To better understand transcriptional regulation of Th2 cell differentiation, we performed CRISPR-Cas9 screens targeting 1,131 TFs. We discovered that activity-dependent neuroprotector homeobox protein (ADNP) was indispensable for immune reactions to allergen. Mechanistically, ADNP performed a previously unappreciated role in gene activation, forming a critical bridge in the transition from pioneer TFs to chromatin remodeling by recruiting the helicase CHD4 and ATPase BRG1. Although GATA3 and AP-1 bound the type 2 cytokine locus in the absence of ADNP, they were unable to initiate histone acetylation or DNA accessibility, resulting in highly impaired type 2 cytokine expression. Our results demonstrate an important role for ADNP in promoting immune cell specialization.